United State Pharmacopeia: Compendial Plastic Standards: Beyond Packaging

Transcription

1 United State Pharmacopeia: Compendial Plastic Standards: Beyond Packaging Desmond G. Hunt, Ph.D. Principle Scientific Liaison November 15, 2016 Denver, CO

2 USP Scientific, independent, volunteer-driven, nonprofit organization Established in 1820 Headquartered in Rockville, MD Facilities in India, China, Brazil, Switzerland 800+ employees Set public quality standards for prescription and over-thecounter medicines, excipients (inactive ingredients), dietary supplements, food ingredients, packaging and labeling Worked closely with FDA and predecessors for >100 years, developing and revising drug quality standards enforceable by FDA Legally recognized in 39+ and standards used in 140+ countries

3 USP <661> Containers Plastics: Test Methods Required in the Current USP <661> Identification Infrared Spectroscopy (IR) Differential Scanning Calorimetry (DSC) Biological Tests USP <87>; Biological Reactivity Test, In Vitro USP <88>; Biological Reactivity Test, In Vivo (if a class designation is required). Physicochemical Tests (water extract) Nonvolatile Residue (NVR); not required for PET/PETG Residue on Ignition (RoI, if NVR > 5 mg); not required for PET/PETG Heavy Metals (HM) Buffering Capacity (BC); not required for PET/PETG Other Tests (for PET and PETG)

4 Plastics Standards Situations in which a Medicine could Contact a Plastic Material During manufacturing (plastics used in the manufacturing suite) During storage/distribution (plastics used in packaging) During clinical use (plastics used in medical devices used to administer the medicine) Thus, USP s interested in plastics has expanded beyond just packaging systems

5 A Starting Point for the USP Standards for Plastics Building safety into a system by using well-characterized and safe materials of construction (Quality by Design). The testing required to select and qualify a system or a system component is correlated to the risk that the system s finished output is adversely effected by its interaction with the component or system (Risk-based Approach). The USP standard serves as a baseline Should have value in every situation of use, but may not necessarily address every individual situation of use 5

6 Scope and Objectives of USP Standards for Plastics Scope Focus on: Safety Material and component-derived foreign impurities Objectives To provide tests and specifications for the characterization of plastic materials So materials can be rationally selected for use and so that the selection can be justified To provide tests and specifications for the characterization of plastic components So plastic components/systems can be rationally selected for use and that the selection can be justified To provide tests and specifications for the safety qualification of manufacturing, packaging and delivery systems (or their components)

7 The Essence of the Current Strategy for Plastics Standardize at the Materials of Construction level Customize at the Component or System level Component or System Testing for Packaging <661.2> Extractable Guidance <1663> Leachable Guidance <1664> Component or System Testing for Devices Characterization of Materials of Construction <661.1> Component or System Testing for Manufacturing

8 <661> Plastic Packaging Systems and their Materials of Construction <661> Plastic Packaging Systems and their Materials of Construction <661.1> Plastic Material of Construction <661.2> Plastic Packaging Systems for Pharmaceutical Use - Identification - Biological Activity - Physico-chemical Tests - Extractable Metals - Plastic Additives - Biological Activity - Physico-chemical Tests - Safety Assessment (Extractables/Leachables)

9 <661.1> Plastic Materials of Construction Comparison of Testing Required for Various Dosage Forms Test Parameter Oral and Topical Dosage Forms All Other Dosage Forms Chemical Tests Identification DSC/IR DSC/IR Physicochemical Tests Extractable Metals Polymer Additives Water extraction: UV absorbance, Acidity/alkalinity TOC Acid extraction: ICP analysis for targeted and relevant metals Proper Reference to Indirect Food Additive Regulations, CFR Biological Reactivity In Vitro per USP <87> Required Required Water extraction: UV absorbance, Acidity/alkalinity TOC Acid extraction: ICP analysis for targeted and relevant metals Direct chemical testing In Vivo per USP <88> Not required Required as needed to obtain plastic classification

10 <661.2> Plastic Packaging Systems for Pharmaceutical Use Comparison of Testing Required for Various Dosage Forms Test Parameter Oral and Topical Dosage Forms All Other Dosage Forms Physicochemical Tests Chemical Assessment Extractables and Leachables (Reference to <1663> and <1664>) Chemical Tests Water extraction: UV absorbance, acidity/alkalinity TOC Risk-based testing* Water extraction: UV absorbance, acidity/alkalinity TOC Risk-based testing* Biological Reactivity In Vitro per USP <87> Required Required In Vivo per USP <88> Not required Required as needed to obtain plastic classification *Alternative testing strategies for chemical safety assessment may be appropriate in justified circumstances, subject to agreement by an appropriate regulatory authority

11 Chapter Status Chapters became official May 1, 2016 Proposed revision to <661.1> and <661.2> in PF 42 (4) July 2016 Scope was revised to better clarify intent <661.1> <661.2> Proposed revision to remove of the Biological Reactivity requirement for materials and packaging used for oral and topical drug products <661.1> <661.2> Proposed addition of the Spectral Transmission Test in <661.2> Test currently resides in <671> Container Performance Testing

12 <661.1> PF 42 (4) July 2016 Current Materials Polyvinyl Chloride, Plasticized Polyethylene Cyclic Olefin Polyethylene Terephthalate Polyethylene Terephthalate G Polyamide 6 (Nylon) Polycarbonate Polyethylene vinyl acetate Polyvinyl Chloride, Non Plasticized Future Materials Acrylonitrile butadiene styrene Polybutylene terephthalate Poly(methylmethacrylate) Polystyrene Polysulfone Polytetrafluoroethylen Polyurethane

13 United States Pharmacopeia: USP GENERAL CHAPTER <661.3>: PLASTIC COMPONENTS AND SYSTEMS USED TO MANUFACTURE PHARMACEUTICAL DRUG PRODUCTS

14 <661.3> Plastic Components and Systems Used in Pharmaceutical Manufacturing Scope: Parameters covered Active pharmaceutical ingredients and drug products Pharmaceuticals, Small Molecules, Biopharmaceuticals products and Vaccines Single-Use Systems and Multi-Use Systems

15 Introduction to <661.3> <661.3> speaks to the characterization of materials of construction Enabling the selection of proper materials used in manufacturing components <661.3> speaks to the characterization of components Enabling the proper selection of components used in manufacturing operations <661.3> does not speak to the qualification of materials, components or systems Testing performed for the purpose of selection may be relevant to qualification.

16 Introduction to <661.3> Components are further characterized depending on the level of risk associated with their application in a particular manufacturing operation. USP <1661> contains a Risk Evaluation Matrix whose purpose is to classify components and their associated conditions of use into three risk categories. High risk components must be profiled for extractables using a Standard Extraction Protocol (SEP) as provided in <661.3>. Standard extraction protocol, consisting of three solvents and one time/temperature combination. <661.3> provides directions on how to perform extractions for typical types of components

17 The Initial Assessment Figure 1. Initial Assessment Component in Contact with Liquid Stream No No Actions Yes Conduct Initial Assessment Comparator Component/System Established Yes No Actions No Proceed to Risk Assessment

18 Risk Assessment in <661.3> Application of the Risk Evaluation Matrix The Risk Evaluation Matrix considers four dimensions which address the risk that a plastic component will be leached by a process stream to such an extent that process streams could contain potentially impactful extractables. These dimensions include: The duration of contact, The temperature of contact, The chemical composition of the process stream, and The nature of the component s materials of construction. The matrix then considers each dimension separately and assigns a level of risk associated with certain measures relevant to each dimension. Three levels of risk are established (A, B or C). 18

19 Using the Risk Matrix to Drive Testing Table 2. Testing Requirements for Three Risk Levels (Revised) Risk Assessment Testing Requirements Level Level Materials of Construction <661.1> Component or System < 661.3> A Baseline All individual materials of construction comply with <661.1> Biocompatibility <87> (lower for identity as follows: Biocompatibility <87> risk) B C (higher risk) Expanded Baseline Physicochemical characteristics (TOC, UV, Acidity /alkalinity Extractable metals (Additives (by proper reference to 21 CFR Indirect Food Additive regulations) All individual materials of construction comply with <661.1> for identity as follows: Biocompatibility <87> and Class VI <88> Identification Physicochemical characteristics (TOC, UV, Acidity /alkalinity Extractable metals Additives determined by testing Biocompatibility <87> and USP Class VI <88> Extractable Metals Full Same as Expanded Baseline Biocompatibility <87> and Class VI <88> Full Extractables Profiling via Standard Extraction Protocol (Solutions C3, C4 and C5) Bolded entries represent testing required in addition to the testing required in the lower risk levels.

20 The Standard Extraction Protocol for High Risk Situations Standard Extraction Protocol for Components or Systems Designated as Risk Level C Extraction Solvents Solution C3, Acidic Extraction, ph 3 Solution C4, Basic Extraction, ph 10 Solution C5, Organic Extraction, 1/1 (v/v) Ethanol/water General principles and recommended best practices for preforming the extractables assessment of can be found in <1663>.

21 Is/Is Not: Standard Extraction Protocol Aspect Is Is Not Application Components (systems) Materials of Construction High Risk Low or Moderate Risk Purpose Component Selection 1 Component Qualification 1 Focus Objective Aim for the Middle (most commonly encountered) Generate Useful Information Aim for the Extreme (most extreme conditions possible) Generate Worst Case Information Note: (1) Under certain circumstances, information for selection may be appropriate as information for qualification. 21

22 The <661.3> Standard Extraction Protocol Solvents Considering Additional Extraction Solvents 1. Any additional extraction solvent should provide information in addition to information provided by the adopted solvents. 2. Any additional extraction solvent should be analytically expedient. 22

23 The <661.3> Standard Extraction Protocol Solvents What about Water? Water provides no additional information that is not already provided by the ph extreme solvents. What about 5 M NaCl? 5 M NaCl is the weakest extraction solvent (for organics) and provides no additional information that is not already provided by the ph extreme solvents. 5 M NaCl is an analytically challenging solution. What about 1% Polysorbate 80? 50% Ethanol may be an appropriate simulant for 1% PS80. 1% PS80 is an extremely challenging solution to analyze. Thus, there is no compelling reason to include these solvents in the Standard Extraction Protocol. 23

24 The <661.3> Standard Extraction Protocol Solvents What about low ph? Data suggests that ph 3 salt solution and 0.1M phosphoric acid produce similar extractables profiles. Phosphate matrix produces minor analytical challenges. USP would consider a statement that made 0.1M phosphoric acid and ph 3 salt solution interchangeable. What about high ph? In certain situations, 0.5 N NaOH may be a more aggressive extraction solvent than ph 10 buffer. 0.5N NaOH can be an analytically challenging matrix, especially related to instrument wear and tear. 0.5N NaOH may not fit the intent of the SEP to aim for the middle USP considers the issue of the high ph extraction solvent to be open for discussion. 24

25 The <661.3> Standard Extraction Protocol Solvents: Score card 50% Ethanol; Alignment Water, 5 M NaCl, 1% Polysorbate 80; Alignment USP allows for the use of additional solvents at the discretion of the sponsor Low ph; Alignment (interchangeable solvents) High ph; To be resolved 25

26 The Standard Extraction Protocol for High Risk Situations Standard Extraction Protocol for Components or Systems Designated as Risk Level C Extraction Conditions Component Extraction Solutions Extraction Temperature Extraction Duration C3 through C day 7 days 21 days Storage Container X X X Mixing Bag X X X Bioreactor Bag X X X Connector X X X Disconnector X X X Sensor/Valve X X X Molded Parts of Mixers X X X Polymer pump surfaces X X X Tubing X X X Gasket, O-ring X X X Sterilizing Filter X X X Process Filter X X X Tangential flow Filtration X X X Chromatography Column X X X Filling Needle X X X 26

27 Status Expert Panel taking feedback from workshop and PF proposal in May 2016 and revising draft accordingly Revised <661.3> (<665>) to be republished Target PF: 43 (3) May 2017 Comment Deadline: July 31, 2017 Target Official Publication: USP 41 Second Supplement Target Official Date: August 1, 2018

28 Upcoming Revisions/Development <381> Elastomeric Closure for Injection The Expert Panel began working on the revision of <381> in May 2014 Workshop June 19-20, 2017 <87> Biological Reactivity, In vitro, <88> Biological Reactivity, In Vivo3200- The Expert Panel began working on the revision of <87> and <88> in March 2015 <660> Container Glass The USP Glass Expert Panel began work on revising <660> and <1660> in September 2016 Workshop June 19-20, 2017 Metal Packaging Systems and Their Materials of Construction Stakeholder Webinar April 2015 To form Expert Pane early 2017

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